With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs), alcohol abuse is among the top three preventable public health problems in the U.S. and the world. AUDs, commonly referred to as alcoholism, have a complex etiology where chronic alcohol associated neurodegeneration, withdrawal-related anxiety and persistent alcohol craving are predictive of high relapse and poor clinical outcomes. The treatment of AUDs would benefit from a pharmacological approach that could address these overlooked endpoints to improve clinical outcomes. However, of the three drugs currently FDA-approved for the treatment of excessive alcohol consumption, none address neurodegeneration, withdrawal or anxiety. Cannabidiol (CBD) is a drug that could improve these three syndromes. Transdermal drug delivery of cannabinoids is a viable alternative to oral dosing. Most of the cannabinoids are highly metabolized in the liver. The oral bioavailability of CBD is only about 6%, and very low plasma drug levels were detected in CBD oral dose clinical trials. It is highly possible that clinical trials of oral dose cannabinoids in patients have given inconsistent results because of a poor choice of drug dosage form. We hypothesize that a CBD transdermal dosage form can be developed, and that this dosage form could provide therapeutic levels of drug in a future clinical study with alcoholic patients. The long-term hypothesis of the overall project is that CBD will decrease withdrawal related anxiety and control alcohol craving, thereby decreasing high relapse susceptibility in alcoholics by modulating the endocannabinoid system. In the first step towards this goal, a proof of concept evaluation of CBD prodrugs delivered via transdermal microneedles will be conducted. CBD itself does not permeate the skin at a therapeutic rate, unless it is applied as a gel to a large skin surface area, as the area of transdermal application is directly proportional to the delivery rate. Prodrugs are chemically modified parent drugs that are more skin permeable than the parent, and once they cross the stratum corneum quickly separate back into the parent drug and prodrug moiety. AllTranz has preliminary data showing that CBD prodrugs alone do not improve skin permeation, unless the prodrugs are specifically designed for use with microneedles. Additionally, CBD delivery with microneedles alone is not significantly enhanced, as compared to optimized CBD prodrugs for microneedle delivery. Specifically we aim to synthesize prodrugs of CBD that will be very skin permeable in combination with a microneedle device. We then aim to assess their in vitro human skin permeation for optimum flux. In future studies we will develop the prototype product and apply for an IND and begin Phase I clinical trials in healthy controls and alcoholics. The future CBD transdermal system could also be tested in Phase II clinical trials for opiate addiction, analgesic effect, inflammation relief (arthritis), and nausea and vomiting treatment, as there is substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications. PUBLIC HEALTH RELEVANCE: With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs), alcohol abuse is among the top three preventable public health problems in the U.S. and the world. Currently approved pharmacological treatments in the treatment of alcoholism and other types of drug addiction are limited in that they do not address multiple aspects of addiction: craving, neurodegeneration, withdrawal and anxiety. The proposed preclinical research will accelerate testing of cannabidiol (CBD) in an appropriate delivery system to assess its potential benefits as a lead candidate in the search for novel alcoholism and other drug addiction pharmacotherapies. The future CBD transdermal system could also be tested in Phase II clinical trials for analgesic effect, inflammation relief, and nausea and vomiting treatment, as there is also substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications.